Neurologic and neuropsychiatric disorders such as depression, anxiety, amyotrophic lateral sclerosis, and central nervous system injuries, to name a few, afflict millions of people every year resulting in a multitude of symptoms including weight change, decreased energy, headaches, digestive problems, chronic pain, paralysis, and in certain instances, death.
One class of growth factors proposed as a treatment for neurologic and neuropsychiatric disorders are neurotrophins, which include brain-derived neurotrophic factor (BDNF). BDNF is believed to have neurotrophic action on various neuronal populations including sensory neurons, motor neurons, dopaminergic neurons of the substantia nigra, and cholinergic neurons of the basal forebrain, which are involved in several neurologic and neuropsychiatric disorders. Preclinical evidence indicates that BDNF might be useful as a therapeutic agent for various neurologic and neuropsychiatric disorders; however, the in vivo instability of such a peptide and its inability to effectively cross the blood brain barrier limits its usefulness.
Because such proposed BDNF therapies have not shown much success in clinical trials, focus has shifted to methods of activating known BDNF targets. One such target is the TrkB receptor tyrosine kinase—also known as BDNF/NT-3 growth factor receptor or neurotrophic tyrosine kinase, receptor, type 2, a protein that in humans is encoded by the NTRK2 gene—which acts as the transmembrane protein receptor responsible for receiving BDNF signals and initiating intracellular signaling cascades that culminate in a cellular response. BDNF binding to TrkB triggers its dimerization through conformational changes and autophosphorylation of tyrosine residues in its intracellular domain, resulting in activation of the three major signaling pathways involving mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K) and phospholipase C-g1 (PLC-g1). Inactivation of TrkB receptors in mice mimic behavioral defects observed in mice heterozygous for a mutant BDNF allele, including behavioral defects consistent with depression, as well as severe hyperphagia and obesity. This and other evidence from studies support a model whereby TrkB-mediated activation of the BDNF pathway is required for elevated neurogenesis in the hippocampus, a mechanism likely underlying the efficacy of antidepressant treatments. Thus, molecules capable of activating TrkB are attractive candidates as therapeutics for various neurologic, neuropsychiatric, and metabolic disorders.
The small molecule 7,8-dihydroxyflavone has been identified as being capable of binding and triggering the activation of TrkB receptors. This compound exerts neuroprotective effects on mice when injected intraperitoneally, indicating that 7,8-dihydroxyflavone is capable of traversing the blood brain barrier. Certain compounds are described further in (Jang et al., 2010; PCT Appl. Nos. US2009/051535; US2009/051966). Thus, there exists a need to identify improved dihydroxyflavone analogues that possess TrkB agonizing capabilities for the treatment of neurotrohpin-derived disorders.